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.

Gray Matter Volume Decrease Distinguishes Schizophrenia From Bipolar Offspring During Childhood and Adolescence

“…Our SzO sample also exhibited significant grey matter volume reduction in a cluster located in the left inferior frontal gyrus; abnormalities in this region have been extensively identified in schizophrenia 33 and in genetic risk youth 13,34,35 . This cluster extended to the anterior insula: insular volume reduction, and especially the anterior subregion, 36 has been extensively implicated in the neuropathology of schizophrenia and in prodromal patients who later transition to psychosis 37,38 , in whom it has been associated with baseline negative symptoms 37 .…”

“…Although both samples are first-degree relatives of patients with schizophrenia, our sample of SzO differs from the young schizophrenia siblings 35,39 in that they present clinical markers of heightened risk for the disorder (lower functionality, greater clinical severity, and higher prodromal symptom scores than CcO), thus making it likely that at least a proportion of these participants will go on to develop the disease 40 . This opens the possibility that the regional volumetric abnormalities that we have observed in SzO may in some cases form part of the preclinical phenotype of disease.…”

Neuroimaging Biomarkers for Psychosis

“…While subtle brain structure alterations, particularly in frontotemporal regions, are already seen in FHR adolescents [51], cortical gray matter thickness reductions and third ventricle enlargement appear to characterize the transition from the prodrome to the first psychotic episode [52]. Interestingly, relatives who do not progress to psychosis appear to even have a reversal of their brain structure alterations [53]. During the early course of SZ, there appears to be further progressive reduction of superior temporal cortices [25].…”

Cognitive intervention in early psychosis — preserving abilities versus remediating deficits

“…This derives from the notion that individuals at heightened risk for a schizophrenia-spectrum disorder (but who do not develop the illness) show a normalisation of abnormalities as they mature into adulthood. This is evidenced in studies examining trajectories of brain development in the unaffected siblings of childhood schizophrenia cases [60][61][62] (for discussion: 10,11,16]). Specifically, abnormalities found in childhood and early adolescence normalise during adolescence, including evidence of increased brain volumes and brain connectivity.…”