Normalization of cortical gray matter deficits in nonpsychotic siblings of patients with childhood-onset schizophrenia

Abstract

Objective: Cortical gray matter (GM) abnormalities in patients with childhood-onset schizophrenia (COS) progress during adolescence ultimately localizing to prefrontal and temporal cortices by early adult age. A previous study of 52 nonpsychotic siblings of COS probands had significant prefrontal and temporal GM deficits that appeared to "normalize" by age 17 years. Here we present a replication with nonoverlapping groups of healthy full siblings and healthy controls.

Method: Using an automated measure and prospectively acquired anatomical brain magnetic resonance images, we mapped cortical GM thickness in nonpsychotic full siblings (n = 43, 68 scans; ages 5 through 26 years) of patients with COS, contrasting them with age-, gender-, and scan interval-matched healthy controls (n = 86, 136 scans). The false-discovery rate procedure was used to control for type I errors due to multiple comparisons.

Results: As in our previous study, young nonpsychotic siblings (<17 years) showed significant GM deficits in bilateral prefrontal and left temporal cortices and, in addition, smaller deficits in the parietal and right inferior temporal cortices. These deficits in nonpsychotic siblings normalized with age with minimal abnormalities remaining by age 17.

Conclusions: Our results support previous findings showing nonpsychotic siblings of COS probands to have early GM deficits that ameliorate with time. At early ages, prefrontal and/or temporal loss may serve as a familial/trait marker for COS. Late adolescence appears to be a critical period for greatest localization of deficits in probands or normalization in nonpsychotic siblings.

FIGURE 1

(A) Comparison of cortical gray matter (GM) thickness (right and left hemisphere) of nonpsychotic siblings of patients with childhood-onset schizophrenia (COS) (n = 43, 68 scans) versus age-, gender-, and scan interval–matched healthy controls (n = 83, 136 scans) between ages 5 and 26 years. Note: Nonpsychotic siblings show significant GM deficits in bilateral prefrontal and left temporal cortices with smaller deficits in the parietal cortices and right inferior temporal cortices. These deficits in nonpsychotic siblings normalize with age, with no abnormalities remaining by age 20 years. Color bar shows the t statistic with the threshold to control for multiple comparisons using the false-discovery rate procedure with q = 0.05. (B) GM thickness of COS nonpsychotic siblings (n = 52, 113 scans) compared with healthy controls (n = 52, 108 scans) between ages 7 and 26 years. Note: Cortical GM thickness is adjusted for mean cortical thickness. These data are published elsewhere and are used here only for visual comparison with the GM developmental pattern of the current study (A).

FIGURE 2

Longitudinal trajectories (slopes) of selected regional cortical gray matter (GM) thickness in nonpsychotic siblings of patients with childhood-onset schizophrenia (COS) compared with those for the same regions for healthy controls, showing group × age interaction effects. Note: Siblings of patients with COS ”normalize” by age 17 years (by slower thinning) in the left prefrontal cortices (A) (df = 71, t = 3.59, p < .001) by age 16 years in the left middle temporal cortices (B) (df = 71, t = 3.78, p < .001), and right prefrontal cortices (C) (df = 71, t = 3.54, p < .001). Graphs represent region of interest analyses at selected regions. Color bar shows the t statistic with the threshold to control for multiple comparisons using the false-discovery rate procedure with q = 0.05.