Twelve Year Longitudinal Trajectories Of Neuroanatomy, Functional Connectivity And Neuropsychological Function In 22Q11.2 Deletion Syndrome: Prediction To Psychosis

Abstract

We conducted a twelve-year longitudinal study of neuroanatomic, neurofunctional and neuropsychological development in youth with 22q11.2 deletion syndrome (22q11DS). Participants, consisting of 88 youth with 22q11DS, 33 unaffected siblings, and 32 community controls, were recruited to our academic medical center from throughout North America, and were followed every three years for four timepoints. Mean age in years at the first timepoint was 11.9; second timepoint, 15.1; third timepoint, 18.1; fourth timepoint, 21.2. High resolution MRI scans and standard neuropsychological measures were administered at all timepoints. Trajectories of cortical thickness and surface area were measured with FreeSurfer, V.5.1. Functional connectivity (at the fourth timepoint only) was measured with the Functional Connectivity Toolbox (CONN) in Matlab. Positive symptoms of psychosis were measured with the Positive Symptom Subscale of the Structured Interview for Prodromal Symptoms (SIPS). Longitudinal linear mixed model regression analyses were conducted, and results were corrected for multiple comparisons. Relative to controls, probands displayed significantly slower rates of longitudinal change in cortical thickness of the superior parietal lobule and precuneus (p-values <0.01). Moreover, functional connectivity between superior parietal lobule and temporal regions were disrupted in probands relative to controls (p < 0.02). Parietal lobe trajectories also predicted Time 4 positive prodromal symptoms (p<0.01) in the probands. Over time, probands also exhibited slower rates of improvement in scores on visual working memory (p=0.001) and auditory/verbal learning (p=0.002) relative to their peers. Decrements in auditory/verbal learning were associated with Time 4 positive prodromal symptoms (p=0.01), as were decrements in the executive skill of set-shifting (p=0.001) and in sustained attention (p=0.006). We conclude that aberrant longitudinal alterations in parietal cortical thickness / connectivity, as well as decrements in auditory/verbal learning, executive function and sustained attention may represent biomarkers for the eventual onset of prodromal psychosis in 22q11DS.