Delayed White Matter Growth Trajectory in Young Nonpsychotic Siblings of Patients With Childhood-Onset Schizophrenia

Abstract

Context Nonpsychotic siblings of patients with childhood-onset schizophrenia (COS) share cortical gray matter abnormalities with their probands at an early age; these normalize by the time the siblings are aged 18 years, suggesting that the gray matter abnormalities in schizophrenia could be an age-specific endophenotype. Patients with COS also show significant white matter (WM) growth deficits, which have not yet been explored in nonpsychotic siblings. Objective To study WM growth differences in non-psychotic siblings of patients with COS. Design Longitudinal (5-year) anatomic magnetic resonance imaging study mapping WM growth using a novel tensor-based morphometry analysis. Setting National Institutes of Health Clinical Center, Bethesda, Maryland. Participants Forty-nine healthy siblings of patients with COS (mean [SD] age, 16.1[5.3] years; 19 male, 30 female) and 57 healthy persons serving as controls (age, 16.9[5.3] years; 29 male, 28 female). Intervention Magnetic resonance imaging. Main Outcome Measure White matter growth rates. Results We compared the WM growth rates in 3 age ranges. In the youngest age group (7 to <14 years), we found a significant difference in growth rates, with siblings of patients with COS showing slower WM growth rates in the parietal lobes of the brain than age-matched healthy controls (false discovery rate, q = 0.05; critical P = .001 in the bilateral parietal WM; a post hoc analysis identified growth rate differences only on the left side, critical P =.004). A growth rate difference was not detectable at older ages. In 3-dimensional maps, growth rates in the siblings even appeared to surpass those of healthy individuals at later ages, at least locally in the brain, but this effect did not survive a multiple comparisons correction. Conclusions In this first longitudinal study of nonpsychotic siblings of patients with COS, the siblings showed early WM growth deficits, which normalized with age. As reported before for gray matter, WM growth may also be an age-specific endophenotype that shows compensatory normalization with age.

A schizophrenia risk gene, ZNF804A, is associated with brain white matter microstructure

“…The finding in the right parietal lobe is consistent with DTI findings in schizophrenia, which have demonstrated delayed growth trajectories in parietal white matter of patients with childhood-onset schizophrenia (Gogtay et al, 2008) and their siblings (Gogtay et al, 2012), as well as lower parietal white matter FA in adult schizophrenia patients (Ardekani et al, 2003), including never medicated patients with a first psychotic episode (Cheung et al, 2011) and patients with deficit schizophrenia (Rowland et al, 2008). Although the current sample consisted of participants without schizophrenia or other psychotic disorders, the lower FA by increased risk allele dosage is consistent with the observed associations between compromised parietal white matter (micro)structure and schizophrenia, and ZNF804A being a risk gene for schizophrenia.…”

Neuroimaging findings from childhood onset schizophrenia patients and their non-psychotic siblings

“…tuning out white noise), which, though not directly related to the illness, may be related to underlying pathology (Freedman et al, 1987). Non-psychotic siblings of COS patients share a number of characteristic abnormalities with their affected relatives, including differences in cerebral volume, gray matter thickness, and white matter growth (Gogtay et al, 2007; Gogtay et al, 2012; Gogtay et al, 2003). …”

“…The volume normalization may help explain inconsistent results from similar studies of cortical thickness in healthy siblings of adult-onset patients (Boos et al, 2012), as sibling cortical thickness seems to depend on the age of the sibling sample. Furthermore, siblings of COS patients have also been shown to exhibit deficits in white matter growth during adolescence at early stages in life, however the growth rate normalizes by adulthood in healthy siblings, suggesting that white matter growth represents an endophenotype (Gogtay et al, 2012). One DTI study has also examined regions of interest in non-psychotic siblings of COS patients, demonstrating deficits in fractional anisotropy in the bilateral cuneus, a characteristic shared between patients and their siblings (Moran et al, 2015).…”

DTI microstructural abnormalities in adolescent siblings of patients with childhood-onset schizophrenia

“…Gogtay et al (2012) and Moran et al (2015) found a delayed white matter growth trajectory and decreased FA in adolescent COS siblings, Boos et al (2013) and Hoptman et al (2008), found increased FA in adult first-degree relatives of AOS, while others (Harms et al, 2015;Koivukangas et al, 2015) found no differences in AOS relatives compared to controls.…”

“…Thus, the deficit in white matter directionality that has been found in adult relatives of patients with schizophrenia may reflect an increased rate of loss of white matter integrity which is not yet apparent in the adolescent relatives of COS patients. There is also some preliminary evidence from a longitudinal study of siblings of COS patients that white matter growth is abnormal during development but normalizes with age (Gogtay et al, 2012).…”