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Original Investigation |

Brain Differences in Infants at Differential Genetic Risk for Late-Onset Alzheimer Disease:  A Cross-sectional Imaging Study

Douglas C. Dean III, MSc1; Beth A. Jerskey, PhD2; Kewei Chen, PhD3,4,5,6; Hillary Protas, PhD3,6; Pradeep Thiyyagura, MS3,6; Auttawat Roontiva, MS3,6; Jonathan O'Muircheartaigh, PhD1,7; Holly Dirks, BSc1; Nicole Waskiewicz, BSc1; Katie Lehman, BSc1; Ashley L. Siniard, PhD6,9; Mari N. Turk, PhD9; Xue Hua, PhD10; Sarah K. Madsen, BS10; Paul M. Thompson, PhD10; Adam S. Fleisher, MD3,6,8; Matthew J. Huentelman, PhD6,9; Sean C. L. Deoni, PhD1; Eric M. Reiman, MD3,6,9,11
[+] Author Affiliations
1Advanced Baby Imaging Lab, School of Engineering, Brown University, Providence, Rhode Island
2Alpert Medical School of Brown University, Providence, Rhode Island
3Banner Alzheimer’s Institute, Phoenix, Arizona
4Department of Mathematics, Arizona State University, Tempe
5Department of Radiology, University of Arizona School of Medicine, Tucson
6Arizona Alzheimer’s Consortium, Phoenix
7Department of Neuroimaging, King’s College London, Institute of Psychiatry, London, England
8Department of Neurology, University of California, San Diego School of Medicine, San Diego
9Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona
10Imaging Genetics Center, Laboratory of Neuro Imaging, Department of Neurology, University of California, Los Angeles School of Medicine, Los Angeles
11Department of Psychiatry, University of Arizona School of Medicine, Phoenix
JAMA Neurol. 2014;71(1):11-22. doi:10.1001/jamaneurol.2013.4544.
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Importance  Converging evidence suggests brain structure alterations may precede overt cognitive impairment in Alzheimer disease by several decades. Early detection of these alterations holds inherent value for the development and evaluation of preventive treatment therapies.

Objective  To compare magnetic resonance imaging measurements of white matter myelin water fraction (MWF) and gray matter volume (GMV) in healthy infant carriers and noncarriers of the apolipoprotein E (APOE) ε4 allele, the major susceptibility gene for late-onset AD.

Design, Setting, and Participants  Quiet magnetic resonance imaging was performed at an academic research imaging center on 162 healthy, typically developing 2- to 25-month-old infants with no family history of Alzheimer disease or other neurological or psychiatric disorders. Cross-sectional measurements were compared in the APOE ε4 carrier and noncarrier groups. White matter MWF was compared in one hundred sixty-two 2- to 25-month-old sleeping infants (60 ε4 carriers and 102 noncarriers). Gray matter volume was compared in a subset of fifty-nine 6- to 25-month-old infants (23 ε4 carriers and 36 noncarriers), who remained asleep during the scanning session. The carrier and noncarrier groups were matched for age, gestational duration, birth weight, sex ratio, maternal age, education, and socioeconomic status.

Main Outcomes and Measures  Automated algorithms compared regional white matter MWF and GMV in the carrier and noncarrier groups and characterized their associations with age.

Results  Infant ε4 carriers had lower MWF and GMV measurements than noncarriers in precuneus, posterior/middle cingulate, lateral temporal, and medial occipitotemporal regions, areas preferentially affected by AD, and greater MWF and GMV measurements in extensive frontal regions and measurements were also significant in the subset of 2- to 6-month-old infants (MWF differences, P < .05, after correction for multiple comparisons; GMV differences, P < .001, uncorrected for multiple comparisons). Infant ε4 carriers also exhibited an attenuated relationship between MWF and age in posterior white matter regions.

Conclusions and Relevance  While our findings should be considered preliminary, this study demonstrates some of the earliest brain changes associated with the genetic predisposition to AD. It raises new questions about the role of APOE in normal human brain development, the extent to which these processes are related to subsequent AD pathology, and whether they could be targeted by AD prevention therapies.

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Figure 1.
Derivation of MWF Estimates

Each voxel within the image (A) is assumed to comprise water trapped within the lipid bilayers of the myelin sheath in chemical exchange with intracellular and extracellular water (B), as well as a third nonexchanging “free” water compartment attributable to cerebral spinal fluid. mcDESPOT (multi-component Driven Equilibrium Single Pulse Observation of T1 and T2) processing fits a mathematical form of this tissue model to the acquired data (C) to derive the relaxation times and volume fractions of each compartment. The volume fraction of the myelin water is termed the myelin water fraction (D). MRI indicates magnetic resonance imaging and SPGR, spoiled gradient recalled echo images.

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Figure 2.
Differences Between Infant Apolipoprotein E ε4 Carriers and Noncarriers in Regional Myelin Water Fraction (MWF), a Measure of White Matter Myelin Content

First row: Between-group MWF differences using data from the entire cohort of 2- to 25-month-old infants. Second row: Between-group MWF differences using data from the subset of infants younger than 6 months. Third row: Overlap of regional MWF differences observed in initial and subset analyses. Compared with their respective noncarrier groups, the 2- to 26-month-old and 2- to 6-month-old ε4 carrier groups had reduced MWFs in white matter regions that mature earlier, including optic radiations, corticospinal tracts, and splenium of the corpus callosum, and increased MWF in frontal white matter regions that mature later, including frontal white matter, the corona radiata, and genu of the corpus callosum (P < .001, uncorrected for multiple comparisons). The magnitude and atlas locations of maximally significant differences in regional MWF are shown in Table 1.

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Figure 3.
Differences Between Infant Apolipoprotein E ε4 Carriers and Noncarriers in Regional Gray Matter Volumes (GMVs)

Compared with noncarriers, 6- to 22-month-old ε4 carriers had significantly reduced GMVs in the bilateral precuneus, posterior/middle cingulate, and occipitotemporal regions (as shown in blue) and in a left lateral temporal region (not shown, because it is too deep to be projected onto the cortical surface), which are preferentially affected in the later preclinical and clinical stages of Alzheimer disease, and significantly greater GMVs (in red) in bilateral medial and lateral frontal regions (P < .001, uncorrected for multiple comparisons). Statistical maps are projected onto the medial and lateral surfaces of a spatially standardized 12-month-old infant’s brain. The magnitude and atlas locations of maximally significant differences in regional GMV are shown in Table 1.

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Figure 4.
Associations Between Myelin Water Fraction (MWF) and Age in the Infant Apolipoprotein E ε4 Carrier and Noncarrier Groups

Top: Regions in which the associations between MWF, a measure of myelin content, and age are significantly different in the 2- to 25-month-old ε4 carrier and noncarrier groups The extensive white matter regions with a significantly attenuated association between MWF and age in the ε4 carrier group are shown in blue; they include optic radiations, corticospinal tracts, and splenium of the corpus callosum, which are known to mature in the earlier stages of brain development. The more limited white matter regions with a significantly stronger association between MWF and age in the ε4 carrier group are shown in orange; they include frontal and associated white matter regions that are known to mature in the later stages of brain development. Bottom: Mean age-related MWF trajectories and their corresponding bootstrap resampling distributions in the 2- to 25-month-old ε4 carrier and noncarrier groups are shown for whole-brain white matter, left optic radiation, and genu of corpus callosum regions of interest. Associations between MWF and age in these regions of interest were significantly attenuated in the ε4 carrier group.

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