Altered Cellular White Matter But Not Extracellular Free Water on Diffusion MRI in Individuals at Clinical High Risk for Psychosis

Objective: Detecting brain abnormalities in clinical high-risk populations before the onset of psychosis is important for tracking pathological pathways and for identifying possible intervention strategies that may impede or prevent the onset of psychotic disorders. Co-occurring cellular and extracellular white matter alterations have previously been implicated after a first psychotic episode. The authors investigated whether or not cellular and extracellular alterations are already present in a predominantly medication-naive cohort of clinical high-risk individuals experiencing attenuated psychotic symptoms. Methods: Fifty individuals at clinical high risk, of whom 40 were never medicated, were compared with 50 healthy control subjects, group-matched for age, gender, and parental socioeconomic status. 3-T multishell diffusion MRI data were obtained to estimate free-water imaging white matter measures, including fractional anisotropy of cellular tissue (FA(T)) and the volume fraction of extracellular free water (FW). Results: Significantly lower FA(T) was observed in the clinical high-risk group compared with the healthy control group, but no statistically significant FW alterations were observed between groups. Lower FA(T) in the clinical high-risk group was significantly associated with a decline in Global Assessment of Functioning Scale (GAF) score compared with highest GAF score in the previous 12 months. Conclusions: Cellular but not extracellular alterations characterized the clinical high-risk group, especially in those who experienced a decline in functioning. These cellular changes suggest an early deficit that possibly reflects a predisposition to develop attenuated psychotic symptoms. In contrast, extracellular alterations were not observed in this clinical high-risk sample, suggesting that previously reported extracellular abnormalities may reflect an acute response to psychosis, which plays a more prominent role closer to or at onset of psychosis.