Poster No:
698
Submission Type:
Abstract Submission
Authors:
Michael Gregory1, J. Shane Kippenhan1, Tiffany Nash1, Madeline Garvey2, Carolyn Mervis3, Daniel Eisenberg4, Shau-Ming Wei1, Philip Kohn4, Peter Schmidt1, Karen Berman4
Institutions:
1NIMH, Bethesda, MD, 2NIMH, Washington, DC, 3University of Pennsylvania, Philadelphia, PA, 4NIMH, Bethesta, MD
First Author:
Co-Author(s):
Introduction:
Hemideletions and duplications of ~1.55 Mb at chromosomal locus 7q11.23 cause Williams syndrome (WS) or 7q11.23 duplication syndrome (Dup7), respectively. Because the underlying genetics are well-defined and circumscribed (the same genes are affected in >95% of individuals) and the neurobehavioral phenotypes are well-defined, these reciprocal, rare neurodevelopmental disorders can serve as elegant natural experiments to better understand how genetic changes may impact complex behaviors. People with WS are characterized by marked visuospatial construction deficits, increased social drive, and mild to moderate intellectual disability, with relative sparing of language. In contrast, people with Dup7 are characterized by social avoidance and shyness with moderate to severe speech delay, but relatively preserved visuospatial abilities. Recent advances in machine learning methods together with the pooling of large-scale normative datasets have enabled quantitative estimations of the biological age of the brain in an individual based on structural neuroimaging measures. The difference between "brain age" and chronological age has been associated with cognitive abilities, though this effect may depend on the developmental stage of an individual: in children, older estimated brain age has been related to better cognitive performance, whereas in adults, older estimated brain age is associated with aging and cognitive decline. Here, we collected longitudinal structural neuroimaging from a developing sample of children with WS and Dup7 and from typically developing children (TDs) to assess how 7q11.23 copy number variation might alter brain age.
Methods:
MR imaging was carried out approximately every two years in 28 participants with WS (70 visits, mean age 12.2 +/- 4.4 years, 19 females), 16 participants with Dup7 (34 visits, mean age 14.0 +/- 3.2 years, 9 females), and 121 TD children (355 visits, mean age 12.3 +/- 3.1 years, 47 females). For each visit, three structural scans were averaged together, N3-intensity normalized, and processed through Freesurfer 7.1.1's recon-all pipeline. Mean cortical thickness and average surface area values were extracted from 68 cortical regions (i.e., 34 bilateral ROIs) in the Desikan-Killiany atlas and 14 subcortical volume measures in the Aseg atlas. Brain age predictions, based on these neuroanatomical features, and the difference between brain age and chronological age, were computed in males and females separately, using the CentileBrain normative dataset based on 37,407 individuals (https://centilebrain.org). Spline models of predicted brain age were computed for each group using the gamm4 R package and differences as related to 7q11.23 copy number variation were tested.
Results:
Brain age was significantly associated with 7q11.23 copy number in males (p=0.04), but not in females (p=0.4). Interestingly, in males, both WS and Dup7 groups showed similar developmental trajectories with shallower slopes than TDs, indicating slower brain maturation. However, children with WS showed brain age that was similar to TD children at young ages but thereafter lagged behind through development, whereas individuals with Dup7 showed advanced brain age at younger ages but matured more slowly than TD children. In females, though between-group differences were not statistically significant, children with WS and Dup7 tended to show slower developmental trajectories than TDs children.
Conclusions:
Here, we describe preliminary results showing differences in developmental trajectories of estimated brain age that are associated with 7q11.23 copy number variations. In both sexes, individuals with 7q11.23 copy number variation appeared to have slower brain maturation during development than their typically developing peers, an effect that was stronger in males. Future work will investigate the regional nature of these findings and their relation to key neurobehavioral features of these syndromes, including social affinity and visuospatial abilities.
Disorders of the Nervous System:
Neurodevelopmental/ Early Life (eg. ADHD, autism)
Genetics:
Neurogenetic Syndromes 1
Lifespan Development:
Early life, Adolescence, Aging
Lifespan Development Other 2
Modeling and Analysis Methods:
Classification and Predictive Modeling
Keywords:
STRUCTURAL MRI
Other - Williams syndrome; 7q11.23 duplication syndrome; Copy Number Variation; Brain Age; Centile Brain
1|2Indicates the priority used for review
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